Cancer cells have developed highly regulated processes to meet the metabolic demands of rapid cell growth. Unlike normal cells, which utilize mitochondrial oxidative phosphorylation to generate ATP needed for cellular processes, most cancer cells instead rely on aerobic glycolysis for ATP generation even under aerobic conditions. (Heiden et al., Science 324, 1029 (2009)). Further, cancer cells alter the metabolism of major classes of macromolecules, including carbohydrates, lipids and nucleic acids, to increase biosynthesis of macromolecules and maintain redox homeostasis. (Cairns et al., Nature Reviews Cancer 11, 85-95 (2011)). These altered cellular metabolisms allow cancer cells to grow and reproduce within a stressful and dynamic microenvironment that would otherwise have blocked proliferation.
Cancer cells acquire the altered metabolic phenotypes partially through genetic alterations in oncogenes and tumor suppressor genes involved in many key cancer-producing pathways. (Levine et al., Science 330, 1340 (2010)). In addition, dysregulation of posttranslational modifications such as protein phosphorylation and glycosylation also contributes to the metabolic reprogramming of cancer cells. (Slawson et al., Nature Reviews Cancer 11, 678-684 (2011)). Posttranslational modifications are rapid and reversible, and have emerged as critical contributing factors for tumor growth.
Glycosylation of proteins with O-linked β-N-acetylglucosamine (O-GlcNAcylation) is one way of posttranslational modification, which serves as a crucial mechanism for cells to respond to various stimuli, and couples nutrient status and cellular metabolism to the regulation of critical signaling pathways. (Hart et al., Nature 446, 1017 (2007)). O-GlcNAc transferase (OGT) catalyzes the covalent attachment of β-D-N-acetylglucosamine (GlcNAc) sugars to serine or threonine residues of many cytoplasmic proteins important for cancer-relevant processes. Alteration in O-GlcNAcylation allows the cancer cell to evade the cell cycle checkpoint controls and acquire adaptability to the local environment. (Slawson et al., Nature Reviews Cancer 11, 678-684 (2011)). Indeed, OGT and O-GlcNAcylation are elevated in multiple cancer types and reducing OGT levels blocks breast cancer growth and prostate cancer metastasis. (Caldwell et al., Oncogene 29, 2831-2842 (2010); Lynch et al., J. Biol. Chem., 287, 11070 (2012)).
There is a need to develop effective cancer therapeutics targeting the metabolic dependencies of cancer cells. While current treatment such as surgery, radiation, and chemotherapy, alone or in combination, has achieved some limited success, effective treatment of cancer remains a major challenge to modern medicine.